A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2020,（12）
• 所属期刊栏目: ARTICLES
• 页码范围: 1098-1108
• 页数: 11页
• 语种: 英文

摘要

Glucagon-like peptides(GLP-1 and GLP-2)are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors(GLP-1 R and GLP-2R)which are important drug targets for metabolic disorders and Crohn's disease,respectively.Despite great progress in GLP-1 R structure determination,our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive.Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a Gs heterotrimer.To accommodate GLP-2 rather than GLP-1,GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices(TMs)1,5,7 and extracellular loop 1(ECL1).In contrast to GLP-1,the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation.The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2,and the GLP-2 C-terminus closely attaches to ECL1,which is the most protruded among 9 class B G protein-coupled receptors(GPCRs).Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation,especially the middle region.These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.